Nuclear factor κB (“NF-κB”) is a family of inducible transcription factors controlling expression of genes that play important roles in airway inflammation and other inflammatory conditions and diseases, atherosclerosis, blood pressure, and immune response.
Under normal conditions, the NF-κB complex is inactivated in the cytoplasm by binding inhibitors of NF-κB. These inhibitors of NF-κB are referred to as “IκB”. Upon cellular stimulation, for example, with angiotensin II, oxidized low-density lipoproteins, cytokines, or viral pathogens, IκB is phosphorylated and degraded, liberating NF-κB, which enters the nucleus and activates the expression of target genes.
IκB Kinase (“IKK”) is a multisubunit complex that transduces upstream activating signals into the rate-limiting phosphorylation of IκB. More particularly, IKK is composed of 10-12 proteins whose composition is largely unknown. These proteins include catalytic kinases, such as IKKα and IKKβ; regulatory proteins, such as NF-κB essential modulator, which is sometimes referred to as “NEMO”, and IKKγ; and scaffolding proteins, such as IKAP.
Several studies have demonstrated that IKK is required for NF-κB activation. For example, one such study demonstrated that specific peptide inhibitors of IKK block inflammation in mice challenged with lipopolysaccharide (“LPS”).
In view of the above, a need remains for methods and products which can modulate NF-κB activation and, thus, which can be used in the treatment, prevention, or management of inflammatory conditions and diseases and of other conditions, diseases, and processes in which activated NF-κB plays a direct or indirect role. The present invention is directed, in part, to addressing this need.